Programmable liquid, gel and biohybrid compartments and methods of use

Abstract

Nano- to microscale liquid coacervate particles are provided. The liquid coacervate particles are produced by a process including stimulating a population of liquid droplets containing one or a mixture of components to induce a phase separation point of a first component, and maintaining stimulation at the phase separation point to form a coacervate domain of the first component within each of the droplets to form the liquid coacervate particles. The self-assembled nano, meso, micro and macro liquid coacervate particles and related coated substrates can have utility in drug delivery, bioanalytical systems, controlled cell culture, tissue engineering, biomanufacturing and drug discovery.

The invention claimed is: 
     
       1. A method for forming multi-phased coacervate particles comprising:
 providing an aqueous solution comprising a plurality of polymers, wherein the plurality of polymers are miscible in the solution under a first set of conditions and wherein the plurality of polymers comprises
 a first polymer that undergoes phase separation upon a change in solution conditions, wherein the first polymer is a hydrophobic homopolymeric elastin-like polymer (ELP), and 
 a second polymer that undergoes phase separation upon a change in solution conditions, the second polymer comprising an amphiphilic diblock homopolymeric polymer (ELP), wherein the second polymer is a different polymer than the first polymer; and 
 
 altering the solution conditions so that the first and second polymers become immiscible and undergo phase separation and form the multi-phased coacervate particles each comprising at least two, separated, immiscible phases with defined structure, wherein the multi-phased coacervate particles each comprise a coacervate domain having a size of about 50 nm to 20 microns. 
 
     
     
       2. The method of  claim 1  wherein the multi-phased coacervate particle comprises a core-shell architecture. 
     
     
       3. The method of  claim 1  wherein the multi-phased structure comprises a structure other than a core-shell architecture. 
     
     
       4. The method of  claim 1  wherein the first and second phase separations take place sequentially in time. 
     
     
       5. The method of  claim 1  wherein the multi-phased coacervate particle comprises a Janus structure. 
     
     
       6. The method of  claim 1  wherein altering the conditions comprises altering the temperature of the solution. 
     
     
       7. The method of  claim 1  wherein altering the conditions comprises evaporation. 
     
     
       8. The method of  claim 1  wherein altering the conditions comprises changing the solvent quality comprising adding a cosolute to the solution. 
     
     
       9. The method of  claim 1  wherein the first and second polymers are thermally-responsive ELPs and altering the conditions comprises altering the temperature of the solution. 
     
     
       10. The method of  claim 1  wherein the plurality of polymers comprises a third polymer that is miscible in the solution under the first set of conditions and which undergoes phase separation upon a change in solution conditions, the method further comprising:
 altering the conditions so that the third polymer is immiscible in the solution and undergoes phase separation to form at least a third, separated, immiscible phase with defined structure. 
 
     
     
       11. The method of  claim 1  wherein the plurality of polymers comprises n polymers, where n is a number, that are miscible in the solution under the first set of conditions, each capable of undergoing phase separation upon a change in solution conditions, the method further comprising altering the conditions up to n number of times to form a number of immiscible phases in the solution. 
     
     
       12. The method of  claim 11  wherein the step of altering the conditions comprises heating the solution. 
     
     
       13. The method of  claim 1  wherein the plurality of polymers comprises at least two polymers that undergo coacervation at the same time and thus form a blended alloy coacervate domain. 
     
     
       14. The method of  claim 1  further comprising providing a substrate wherein the polymers coacervate on the surface of the substrate. 
     
     
       15. The method of  claim 1  wherein the solution further comprises a bioactive agent. 
     
     
       16. The method of  claim 12  wherein the bioactive agent is selected from the group consisting of a drug, a protein, a peptide, a peptide hormone, a ligand, a cell-signaling; ligand, and an RGD cell binding domain. 
     
     
       17. The method of  claim 1  wherein a bioactive agent is attached to at least one of the polymers. 
     
     
       18. The method of  claim 14  wherein the bioactive agent is selected from the group consisting of a drug, a protein, a peptide, a peptide hormone, a ligand, a cell-signaling ligand, and an RGD cell binding domain. 
     
     
       19. The method of  claim 1 , further comprising crosslinking at least one of the resulting phase separated structures to form a gel containing material. 
     
     
       20. The method of  claim 1  wherein altering the conditions comprises in-situ chemical and physical modification of solution polymers. 
     
     
       21. The method of  claim 20  wherein the chemical modification is selected from (de)methylation or (de)phosphorylation of a polypeptide, click chemistry to (i) attach small chemical moieties or (ii) increase the degree of polymerization via concatenation of polymers. 
     
     
       22. The method of  claim 1 , wherein a mole ratio of the hydrophobic homopolymeric ELP to the amphiphilic diblock homopolymeric ELP is about 1:1 to about 50:1.